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Magnitude of Nonalcoholic Fatty Liver Disease: Western Perspective

  • Author Footnotes
    1 These two authors contributed equally.
    Naga S. Samji
    Footnotes
    1 These two authors contributed equally.
    Affiliations
    Tenova Cleveland Hospital, 2305 Chambliss Ave NW, Cleveland, TN, 37311, USA
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  • Author Footnotes
    1 These two authors contributed equally.
    Rajanshu Verma
    Footnotes
    1 These two authors contributed equally.
    Affiliations
    Tenova Cleveland Hospital, 2305 Chambliss Ave NW, Cleveland, TN, 37311, USA

    Division of Transplant Surgery, Department of Surgery, Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN, 38139, USA
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  • Sanjaya K. Satapathy
    Correspondence
    Address for correspondence: Sanjaya K. Satapathy, Medical Director, Liver Transplantation, Division of Hepatology at Sandra Atlas Bass Center for Liver Diseases, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Associate Professor of Medicine, 400 Community Drive, Manhasset, NY 11030, USA.
    Affiliations
    Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases, Northwell Health, Manhasset, NY, 11030, USA
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  • Author Footnotes
    1 These two authors contributed equally.
      The incidence of nonalcoholic fatty liver disease (NAFLD) is continuing to rise worldwide, and it is estimated that this disquieting trend will continue for another 10–15 years before prevalence begins to decrease. NAFLD is the hepatic manifestation of metabolic syndrome. As obesity, diabetes, and other lifestyle-related diseases continue to rise, the spectrum of NAFLD, e.g., nonalcoholic steatohepatitis, liver fibrosis, liver cirrhosis, liver-related morbidity, and mortality, will increase in parallel. Its widespread prevalence and associated economic burden have drawn significant attention, and a multitude of pharmaceutical companies are participating in active research trying to find a “cure”. Unfortunately, as of now, no targeted treatment exists to treat this condition, and therefore, emphasis has been on its prevention. The current review focuses on the epidemiology, clinical characteristics, risk factors, and clinical outcomes of NAFLD in Western countries. It is important to understand the magnitude of NAFLD and its risk factors in Western countries where the prevalence of NAFLD has now reached epidemic proportions to identify the best strategy to prevent and possibly control this epidemic.

      Keywords

      Abbreviations:

      CKD (chronic kidney disease), NAFLD (nonalcoholic fatty liver disease), NASH (nonalcoholic steatohepatitis), BMI (body mass index), OSA (obstructive sleep apnea), PNPLA3 (patatin-like phospholipase domain–containing protein 3), TM6SF2 (transmembrane 6 superfamily 2)
      With the advent of highly effective medications to eradicate hepatitis C and control hepatitis B, nonalcoholic fatty liver disease (NAFLD) is marching ahead unabated to become the most common chronic liver disease throughout the world. With prevalence of obesity reaching around 40% in the United States, NAFLD, an obvious by-product of obesity, is increasing in parallel and will have far-reaching consequences that will put increased stress on the health-care system in the years to come.
      • Hales C.M.
      • Carroll M.D.
      • Fryar C.D.
      • Ogden C.L.
      Prevalence of obesity among adults and youth: United States, 2015-2016.
      This review article will focus on the magnitude, prevalence, racial distribution, long-term outcomes, rising economic/health-care burden, and impact of NAFLD on liver transplantation and mortality associated with it in the Western world. Worldwide prevalence of NAFLD diagnosed through imaging is 25%, and nonalcoholic steatohepatitis (NASH) is estimated to be around 3–4%. Highest prevalence is found in the Middle East (32%) and South America (31%), while its lowest prevalence is in Africa (14%).
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • Fazel Y.
      • Henry L.
      • Wymer M.
      Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.
      NAFLD prevalence varies significantly depending on the country, race, and ethnicity.

      Prevalence of NAFLD in the Western World

      In the United States, 64 million people are estimated to have NAFLD; of which, 6.65 million have NASH.
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • Fazel Y.
      • Henry L.
      • Wymer M.
      Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.
      • Younossi Z.M.
      • Tampi R.
      • Priyadarshini M.
      • Nader F.
      • Younossi I.M.
      • Racila A.
      Burden of illness and economic model for patients with non-alcoholic steatohepatitis (NASH) in the United States.
      There were estimated 232,000 cases of incident NASH reported in 2017 in the United States.
      • Younossi Z.M.
      • Tampi R.
      • Priyadarshini M.
      • Nader F.
      • Younossi I.M.
      • Racila A.
      Burden of illness and economic model for patients with non-alcoholic steatohepatitis (NASH) in the United States.
      In a smaller study conducted in Manitoba, Canada, incidence of NASH was reported to be between 28 and 36%.
      • Uhanova J.
      • Minuk G.
      • Lopez Ficher F.
      • Chandok N.
      Nonalcoholic fatty liver disease in Canadian first nations and non-first nations patients.
      Prevalence of NAFLD in South America is 30.4%, with up to a third of these individuals progressing to NASH.
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • Fazel Y.
      • Henry L.
      • Wymer M.
      Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.
      • Andrade G.C.
      • Fujise L.H.
      • Santana J.E.F.
      • Oliveira F.
      • Silva Rde C.
      Non-alcoholic fatty liver disease (NAFLD) in different populations: a clinical and epidemiological study - sample of Sao Jose do Rio Preto.
      Depending on the country, the prevalence of NAFLD varies from as low as 13% in Peru to as high as 30% in Brazil.
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • Fazel Y.
      • Henry L.
      • Wymer M.
      Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.
      • Younossi Z.
      • Anstee Q.M.
      • Marietti M.
      • et al.
      Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.
      Most of these studies used abdominal ultrasound and transaminases to estimate the prevalence of NAFLD. Prevalence of NAFLD diagnosed by ultrasound and liver enzymes in Italy was noted to be 23%, the Netherlands 34%, Hungary 23%, and Finland about 41%.
      • Tomic D.
      • Kemp W.W.
      • Roberts S.K.
      Nonalcoholic fatty liver disease: current concepts, epidemiology and management strategies.
      Prevalence of NAFLD seem to be more in UK (46.2%) among all European countries compared to Germany (about 30%), Romania 20%, and Spain 25.8%.
      • Andronescu C.I.
      • Purcarea M.R.
      • Babes P.A.
      Nonalcoholic fatty liver disease: epidemiology, pathogenesis and therapeutic implications.
      As per recent estimates, prevalence of NAFLD in the United States based on liver ultrasound in general population is around 24%.
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • Fazel Y.
      • Henry L.
      • Wymer M.
      Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.
      However, NAFLD is more prevalent in Hispanics (24.1%) compared to African Americans (13.5%), and even among Hispanics, incidence varies based on their country of origin (Mexican 33% vs Dominican 16%).
      • Younossi Z.
      • Anstee Q.M.
      • Marietti M.
      • et al.
      Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.
      • Lazo M.
      • Hernaez R.
      • Eberhardt M.S.
      • et al.
      Prevalence of nonalcoholic fatty liver disease in the United States: the third national health and nutrition examination survey, 1988-1994.
      Bambha et al.
      • Bambha K.
      • Belt P.
      • Abraham M.
      • et al.
      Ethnicity and nonalcoholic fatty liver disease.
      described that Latinos with NASH earned a lower income, ate more carbohydrates, and were less physically active than non-Latino whites.

      Risk Factors for NAFLD and Their Prevalence

      • 1)
        Diet
      The rising prevalence of NAFLD in Western countries has been incriminated to its association with food habits and sedentary lifestyles. Patients with NAFLD often consume a high-fat diet that may be an independent risk factor for the development of NASH.
      • Vilar L.
      • Oliveira C.P.
      • Faintuch J.
      • et al.
      High-fat diet: a trigger of non-alcoholic steatohepatitis? Preliminary findings in obese subjects.
      Additionally, the quality of dietary fats plays a key role in the pathogenesis of NAFLD as shown by the beneficial effect of monounsaturated fatty acids and polyunsaturated fatty acids.
      • Assy N.
      • Nassar F.
      • Nasser G.
      • Grosovski M.
      Olive oil consumption and non-alcoholic fatty liver disease.
      • Capanni M.
      • Calella F.
      • Biagini M.R.
      • et al.
      Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study.
      Westernized dietary patterns, characterized by a high consumption of red meat products, refined grains, pastries, and sugar-sweetened beverages, are associated with higher likelihood or risk of metabolic syndrome, whereas adherence to dietary patterns that are rich in whole grains, fruits, vegetables, legumes, and fish appears to exert a beneficial effect.
      • Andersen C.J.
      • Fernandez M.L.
      Dietary strategies to reduce metabolic syndrome.
      • Martinez-Gonzalez M.A.
      • Martin-Calvo N.
      The major European dietary patterns and metabolic syndrome.
      Much of the data support beneficial effect of Mediterranean diet on both prevention and resolution of the metabolic syndrome
      • Esposito K.
      • Kastorini C.M.
      • Panagiotakos D.B.
      • Giugliano D.
      Mediterranean diet and metabolic syndrome: an updated systematic review.
      and reducing risk and severity of NAFLD.
      • Gelli C.
      • Tarocchi M.
      • Abenavoli L.
      • Di Renzo L.
      • Galli A.
      • De Lorenzo A.
      Effect of a counseling-supported treatment with the Mediterranean diet and physical activity on the severity of the non-alcoholic fatty liver disease.
      Further studies are warranted to confirm these early findings in a larger population of patients and potentially use Mediterranean dietary pattern as an adjunct for treatment of NAFLD in Western population.
      • 2)
        Obesity
      Obesity is defined by a body mass index (BMI) > 30 kg/m2, and morbid obesity is defined as a BMI > 40 kg/m2.
      • Kubik J.F.
      • Gill R.S.
      • Laffin M.
      • Karmali S.
      The impact of bariatric surgery on psychological health.
       Prevalence of obesity is increasing in adults and children and has been described by the World Health Organization as a global epidemic with an estimated 500 million obese adults and 1.5 billion overweight or obese individuals worldwide.
      • Finucane M.M.
      • Stevens G.A.
      • Cowan M.J.
      • et al.
      National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants.
      Prevalence of obesity as per the Centers for Disease Control and Prevention is 39.8% in adults in the USA.
       Mean BMI in US adults has increased from 25.7 to 28.7 for men and from 25.1 to 28.7 for women from 1960s to 2000s with a threefold increase in rates of obesity over this time period.
      • Block J.P.
      • Subramanian S.V.
      • Christakis N.A.
      • O'Malley A.J.
      Population trends and variation in body mass index from 1971 to 2008 in the Framingham heart study offspring cohort.
      As per the CDC, up to 9.8% of US adults have diabetes and 34% are prediabetic.
      NAFLD has been strongly linked to obesity, with a reported prevalence as high as 80% in obese patients and only 16% in individuals with a normal BMI and without metabolic risk factors.
      • Williams C.D.
      • Stengel J.
      • Asike M.I.
      • et al.
      Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study.
      • Bellentani S.
      • Saccoccio G.
      • Masutti F.
      • et al.
      Prevalence of and risk factors for hepatic steatosis in Northern Italy.
      Prevalence of nonalcoholic liver disease in patients with obesity undergoing bariatric surgery is >95% and is about 33–66% in patients with diabetes.
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • et al.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
       Patients with lean NAFLD share similar metabolic profile with insulin resistance and dyslipidemia as in obese patients.
      • Wang A.Y.
      • Dhaliwal J.
      • Mouzaki M.
      Lean non-alcoholic fatty liver disease.
       The prevalence of NAFLD in the US in lean individuals is about 7%.
      • Younossi Z.M.
      • Stepanova M.
      • Negro F.
      • et al.
      Nonalcoholic fatty liver disease in lean individuals in the United States.
      Visceral adiposity has been linked to susceptibility to NAFLD in nonobese subjects as opposed to subcutaneous fat and BMI.
      • Ha Y.
      • Seo N.
      • Shim J.H.
      • et al.
      Intimate association of visceral obesity with non-alcoholic fatty liver disease in healthy asians: a case-control study.
      In a recent study, bariatric surgery resulted in improvement in histopathologic features of disease and resolution of NASH in nearly 85% of patients after 1 year of follow-up.
      • Lassailly G.
      • Caiazzo R.
      • Buob D.
      • et al.
      Bariatric surgery reduces features of non-alcoholic steatohepatitis in morbidly obese patients.
       In a recently published systematic review and meta-analysis, bariatric surgery was found to result in complete resolution of NAFLD in obese patients.
      • Lee Y.
      • Doumouras A.G.
      • Yu J.
      • et al.
      Complete resolution of nonalcoholic fatty liver disease after bariatric surgery: a systematic review and meta-analysis.
      Randomized controlled trials are needed to confirm the therapeutic benefits of bariatric surgery in NAFLD.
      • 3)
        Type 2 diabetes
      The intricate role of the liver in systemic metabolism, insulin resistance, and type 2 diabetes mellitus (T2DM) cannot be overemphasized. Patients with NAFLD are commonly insulin resistant. On the other hand, a large number of patients with T2DM develop NASH as an inflammatory complication of NAFLD. The high incidence of NASH in patients with T2DM leads to further complications, such as cirrhosis and hepatocellular carcinoma, which are increasingly being recognized.
      • Tilg H.
      • Moschen A.R.
      • Roden M.
      NAFLD and diabetes mellitus.
      Both personal and family history of diabetes increases the risk of NASH and fibrosis among patients with NAFLD.
      • Loomba R.
      • Abraham M.
      • Unalp A.
      • et al.
      Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis.
      In fact, family history of diabetes has been proposed as a potential marker for risk stratification of patients with NAFLD (especially among nondiabetics).
      • Loomba R.
      • Abraham M.
      • Unalp A.
      • et al.
      Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis.
      Several prior studies from the NASH Clinical Research Network cohort and several other independent cohorts have consistently shown that diabetes is associated with NASH and advanced fibrosis among patients with NAFLD.
      • Angulo P.
      • Hui J.M.
      • Marchesini G.
      • et al.
      The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD.
      • Neuschwander-Tetri B.A.
      • Clark J.M.
      • Bass N.M.
      • et al.
      Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease.
      • Angulo P.
      • Keach J.C.
      • Batts K.P.
      • Lindor K.D.
      Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis.
      • Marchesini G.
      • Brizi M.
      • Morselli-Labate A.M.
      • et al.
      Association of nonalcoholic fatty liver disease with insulin resistance.
      The presence of diabetes has long-term prognostic significance in patients with liver disease because it is an independent predictor of cirrhosis and hepatocellular carcinoma (HCC).
      • Powell E.E.
      • Cooksley W.G.
      • Hanson R.
      • Searle J.
      • Halliday J.W.
      • Powell L.W.
      The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years.
      • El-Serag H.B.
      • Tran T.
      • Everhart J.E.
      Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.
      • Bugianesi E.
      • Leone N.
      • Vanni E.
      • et al.
      Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.
      • 4)
        Obstructive sleep apnea
      Obstructive sleep apnea (OSA) affects over 4% of the general population and 35–45% of obese individuals.
      • Young T.
      • Palta M.
      • Dempsey J.
      • Skatrud J.
      • Weber S.
      • Badr S.
      The occurrence of sleep-disordered breathing among middle-aged adults.
      • Vgontzas A.N.
      • Tan T.L.
      • Bixler E.O.
      • Martin L.F.
      • Shubert D.
      • Kales A.
      Sleep apnea and sleep disruption in obese patients.
      There is evidence to suggest that OSA is an independent risk factor for NAFLD.
      • Tanne F.
      • Gagnadoux F.
      • Chazouilleres O.
      • et al.
      Chronic liver injury during obstructive sleep apnea.
       Meta-analysis done by Musso et al.
      • Musso G.
      • Cassader M.
      • Olivetti C.
      • Rosina F.
      • Carbone G.
      • Gambino R.
      Association of obstructive sleep apnoea with the presence and severity of non-alcoholic fatty liver disease. A systematic review and meta-analysis.
      showed that OSA is associated with increased risk of NAFLD and that all patients with OSA should be screened for NAFLD and liver fibrosis. Several cohort studies have demonstrated a high incidence of fatigue and OSA symptoms in those with NAFLD.
      • Newton J.L.
      • Jones D.E.
      • Henderson E.
      • et al.
      Fatigue in non-alcoholic fatty liver disease (NAFLD) is significant and associates with inactivity and excessive daytime sleepiness but not with liver disease severity or insulin resistance.
      • Singh H.
      • Pollock R.
      • Uhanova J.
      • Kryger M.
      • Hawkins K.
      • Minuk G.Y.
      Symptoms of obstructive sleep apnea in patients with nonalcoholic fatty liver disease.
      The pathophysiological mechanism leading NAFLD in OSA has been extensively reviewed.
      • Paschetta E.
      • Belci P.
      • Alisi A.
      • Liccardo D.
      • Cutrera R.
      • Musso G.
      OSAS-related Inflammatory Mechanisms of Liver Injury in Nonalcoholic Fatty Liver Disease. 2015.
       Evidence suggests that the pathophysiological alteration in gas exchange (repetitive hypoxemic and hypercapnic events), called chronic intermittent hypoxia (CIH), can lead to increased proinflammatory cytokine production, endothelial dysfunction, oxidative stress, metabolic dysregulation, and insulin resistance.
      • Ciftci T.U.
      • Kokturk O.
      • Bukan N.
      • Bilgihan A.
      The relationship between serum cytokine levels with obesity and obstructive sleep apnea syndrome.
      • Ryan S.
      • Taylor C.T.
      • McNicholas W.T.
      Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome.
      • Christou K.
      • Markoulis N.
      • Moulas A.N.
      • Pastaka C.
      • Gourgoulianis K.I.
      Reactive oxygen metabolites (ROMs) as an index of oxidative stress in obstructive sleep apnea patients.
      Additionally, CIH may trigger liver injury, inflammation, and fibrogenesis.
      • Musso G.
      • Olivetti C.
      • Cassader M.
      • Gambino R.
      Obstructive sleep apnea-hypopnea syndrome and nonalcoholic fatty liver disease: emerging evidence and mechanisms.
      In alignment with this evidence, OSA has also been shown to promote the evolution of NAFLD from steatosis to NASH in an animal model.
      • Piguet A.C.
      • Stroka D.
      • Zimmermann A.
      • Dufour J.F.
      Hypoxia aggravates non-alcoholic steatohepatitis in mice lacking hepatocellular PTEN.
      Several studies have suggested a robust relationship between OSA and NASH.
      • Tanne F.
      • Gagnadoux F.
      • Chazouilleres O.
      • et al.
      Chronic liver injury during obstructive sleep apnea.
      • Aron-Wisnewsky J.
      • Minville C.
      • Tordjman J.
      • et al.
      Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese.
      • Mishra P.
      • Nugent C.
      • Afendy A.
      • et al.
      Apnoeic-hypopnoeic episodes during obstructive sleep apnoea are associated with histological nonalcoholic steatohepatitis.
      • Daltro C.
      • Cotrim H.P.
      • Alves E.
      • et al.
      Nonalcoholic fatty liver disease associated with obstructive sleep apnea: just a coincidence?.
      • Kallwitz E.R.
      • Herdegen J.
      • Madura J.
      • Jakate S.
      • Cotler S.J.
      Liver enzymes and histology in obese patients with obstructive sleep apnea.
      • Polotsky V.Y.
      • Patil S.P.
      • Savransky V.
      • et al.
      Obstructive sleep apnea, insulin resistance, and steatohepatitis in severe obesity.
      • Campos G.M.
      • Bambha K.
      • Vittinghoff E.
      • et al.
      A clinical scoring system for predicting nonalcoholic steatohepatitis in morbidly obese patients.
      A recent study also found association of OSA with advanced NASH histology.
      • Corey K.E.
      • Misdraji J.
      • Gelrud L.
      • et al.
      Obstructive Sleep Apnea Is Associated with Nonalcoholic Steatohepatitis and Advanced Liver Histology.
      In summary, there is evidence to suggest that presence of OSA might alter the natural history of NAFLD, development of NASH, and fibrosis progression.
      • 5)
        Genetic factors
      Epidemiological and genetic studies provide a solid example of heritability of NAFLD and also help clarify some of the variability in NAFLD phenotype and risk of its progression. To date, at least three common genetic variants in the patatin-like phospholipase domain–containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), and glucokinase regulatory protein genes have been robustly linked to NAFLD.
      • Danford C.J.
      • Yao Z.M.
      • Jiang Z.G.
      Non-alcoholic fatty liver disease: a narrative review of genetics.
      PNPLA3, also known as adiponutrin, is a member of the patatin-like phospholipase family. The rs738409 C-> G single-nucleotide polymorphism, encoding the Ile148Met variant protein of PNPLA3, is a well-described genetic determinant of hepatic steatosis.
      • Romeo S.
      • Kozlitina J.
      • Xing C.
      • et al.
      Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.
      Several studies have established a strong link between PNPLA3 and the development of NAFLD.
      • Sookoian S.
      • Pirola C.J.
      Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease.
      • Kovalic A.J.
      • Banerjee P.
      • Tran Q.T.
      • Singal A.K.
      • Satapathy S.K.
      Genetic and epigenetic culprits in the pathogenesis of nonalcoholic fatty liver disease.
      A recent meta-analysis showed significant association between risk of NAFLD and NASH and rs738409 polymorphism in all genetic models.
      • Xu R.
      • Tao A.
      • Zhang S.
      • Deng Y.
      • Chen G.
      Association between patatin-like phospholipase domain containing 3 gene (PNPLA3) polymorphisms and nonalcoholic fatty liver disease: a HuGE review and meta-analysis.
       PNPLA3 polymorphism rs738409 has been associated with NASH as well as with severity of necroinflammatory changes independent of metabolic factors.
      • Verrijken A.
      • Beckers S.
      • Francque S.
      • et al.
      A gene variant of PNPLA3, but not of APOC3, is associated with histological parameters of NAFLD in an obese population.
      Additionally, PNPLA3 has been associated with an increased risk of advanced fibrosis among patients with liver disease and is an independent risk factor for HCC among patients with NASH.
      • Singal A.G.
      • Manjunath H.
      • Yopp A.C.
      • et al.
      The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis.
       NASH was more frequently observed in GG than CC homozygous variant of the gene.
      • Sookoian S.
      • Pirola C.J.
      Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease.
      The rs738409 GG genotype versus the CC genotype was associated with a 28% increase in serum alanine aminotransferase levels. Although its exact biological function is debated, PNPLA3 is highly expressed on the surface of lipid droplets of hepatocytes and adipose tissue. Aberrant function of PNPLA3 rs738409 results in an absence of lipase activity, thus leading to intracellular triglyceride or retinol accumulation in hepatocytes and hepatic stellate cells, respectively.
      • Chamoun Z.
      • Vacca F.
      • Parton R.G.
      • Gruenberg J.
      PNPLA3/adiponutrin functions in lipid droplet formation.
      • He S.
      • McPhaul C.
      • Li J.Z.
      • et al.
      A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis.
      • Huang Y.
      • Cohen J.C.
      • Hobbs H.H.
      Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease.

      Long-Term Outcomes of NAFLD

      The fundamental function of the liver is glucose and lipid metabolism, which is altered in the setting of NAFLD, resulting in pathophysiological effects that extend beyond the liver with significant increase in prevalent and incident cardiovascular disease (CVD), chronic kidney disease (CKD), and T2DM. The magnitude of risk of developing these extrahepatic manifestations parallels the underlying severity of NAFLD, such that patients with NASH appear to be at a greater risk of incident CVD, CKD, and T2DM than those with simple steatosis. PNPLA3, visceral adipose tissue accumulation, dietary intake, and the gut microbiome further modify the risk of developing these extrahepatic manifestations. More recently, NAFLD has been associated with risk of developing colonic neoplasia and reduced bone mineral density.
      • 1)
        Chronic kidney disease
      Prevalence of CKD in the US is 6.9%.
      • Murphy D.
      • McCulloch C.E.
      • Lin F.
      • et al.
      Trends in prevalence of chronic kidney disease in the United States.
      The presence and severity of NAFLD are associated with an increased risk and severity of CKD.
      • Musso G.
      • Gambino R.
      • Tabibian J.H.
      • et al.
      Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis.
       Musso et al.
      • Musso G.
      • Gambino R.
      • Tabibian J.H.
      • et al.
      Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis.
      found a strong correlation between CKD and NASH/NAFLD after adjusting for other traditional risk factors for NASH. Patients with NAFLD have a 40% increased risk of developing CKD.
      • Mantovani A.
      • Zaza G.
      • Byrne C.D.
      • et al.
      Nonalcoholic fatty liver disease increases risk of incident chronic kidney disease: a systematic review and meta-analysis.
      CKD is also a known independent predictor of increased mortality (18.5% in 17 years) in patients with NAFLD.
      • Paik J.
      • Golabi P.
      • Younoszai Z.
      • Mishra A.
      • Trimble G.
      • Younossi Z.M.
      Chronic kidney disease is independently associated with increased mortality in patients with non-alcoholic fatty liver disease.
      NAFLD increases the risk of cardiovascular events independent of the effect of CKD on the same.
      • Chinnadurai R.
      • Ritchie J.
      • Green D.
      • Kalra P.A.
      Non-alcoholic fatty liver disease and clinical outcomes in chronic kidney disease.
      The implication is that routine screening for NAFLD may be warranted in populations with CKD to enable targeted interventions for CVD prevention in higher risk patients. Additionally, the impact of renal function at the time of transplant has shown to have an impact on graft survival. In a recent study, Molnar et al.
      • Molnar M.Z.
      • Joglekar K.
      • Jiang Y.
      • et al.
      Association of pre-transplant renal function with liver graft and patient survival after liver transplantation in patients with nonalcoholic steatohepatitis.
      showed that simultaneous liver-kidney (SLK) recipients with NASH with preserved renal function before liver transplantation had a lower risk of death and functioning graft compared to patients with pretransplant severe renal dysfunction and patients who were SLK recipients.
      • 2)
        Cardiovascular disease
      NAFLD has been associated with both increased CV and all-cause mortality.
      • Luo J.
      • Xu L.
      • Li J.
      • Zhao S.
      Nonalcoholic fatty liver disease as a potential risk factor of cardiovascular disease.
      One Italian study performed with a ten-year follow-up via prospective case–control design demonstrated that patients with NAFLD were at increased risk for CV events, such as acute coronary syndrome and cerebrovascular accident as compared to controls.
      • Fracanzani A.L.
      • Tiraboschi S.
      • Pisano G.
      • et al.
      Progression of carotid vascular damage and cardiovascular events in non-alcoholic fatty liver disease patients compared to the general population during 10 years of follow-up.
      The presence of carotid plaques and hepatic steatosis were the strongest predictors for such events. Most recently, in analysis of the Multi-Ethnic Study of Atherosclerosis study, 728 American NAFLD subjects were prospectively observed and found to have an increased incidence of nonfatal myocardial infarction, cardiac arrest, angina with or without revascularization, and all-cause mortality after median 7.6-year follow-up as compared to controls.
      • Zeb I.
      • Li D.
      • Budoff M.J.
      • et al.
      Nonalcoholic fatty liver disease and incident cardiac events: the multi-ethnic study of Atherosclerosis.
       Among a Finnish cohort observing 268 patients with NAFLD and 720 controls, there was an increase in CV events proportional to the amount of hepatic steatosis as quantified by ultrasound.
      • Pisto P.
      • Santaniemi M.
      • Bloigu R.
      • Ukkola O.
      • Kesaniemi Y.A.
      Fatty liver predicts the risk for cardiovascular events in middle-aged population: a population-based cohort study.
      A subsequent retrospective American study identified NAFLD patients with increased frequency of CV events after five- and ten-year follow-up.
      • Pickhardt P.J.
      • Hahn L.
      • Munoz del Rio A.
      • Park S.H.
      • Reeder S.B.
      • Said A.
      Natural history of hepatic steatosis: observed outcomes for subsequent liver and cardiovascular complications.
      In a recent cross-sectional study involving the third-generation offspring from the Framingham Heart Study, no association existed between CV events and NAFLD, as diagnosed via CT.
      • Mellinger J.L.
      • Pencina K.M.
      • Massaro J.M.
      • et al.
      Hepatic steatosis and cardiovascular disease outcomes: an analysis of the Framingham Heart Study.
      However, the study included significantly more diabetic patients within the CV group, and the ages of these patients were also much older than those of controls who did not develop CV events, limiting interpretation of this study. There was also a low prevalence of CV events overall, as defined by nonfatal MI, heart failure, CVA, transient ischemic attack and peripheral arterial disease in this selective patient population. Despite these drawbacks, there was still an association found between hepatic steatosis and subclinical CV disease, which included coronary artery calcium and abdominal artery calcium, especially among male subjects. A retrospective American study concluded that increasing severity of NAFLD histology correlated with increased liver-related mortality but not all-cause mortality.
      • Matteoni C.A.
      • Younossi Z.M.
      • Gramlich T.
      • Boparai N.
      • Liu Y.C.
      • McCullough A.J.
      Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.
      These 132 NAFLD cases were almost exclusively analyzed in a Caucasian cohort. Moreover, the prevalence of T2DM was lower in patients with isolated hepatic steatosis versus patients with steatohepatitis. A later Swedish prospective cohort study found that NASH was associated with both increased liver-related and all-cause mortality as compared to controls.
      • Ekstedt M.
      • Franzen L.E.
      • Mathiesen U.L.
      • et al.
      Long-term follow-up of patients with NAFLD and elevated liver enzymes.
      Another prospective American study stated that NASH increases liver-related mortality but not overall mortality when compared to all NAFLD patients.
      • Rafiq N.
      • Bai C.
      • Fang Y.
      • et al.
      Long-term follow-up of patients with nonalcoholic fatty liver.
      Independent risk factors for liver-related mortality included T2DM, older age, lower albumin, and elevated alkaline phosphatase levels. In contradiction to these studies, one retrospective, American study revealed that hepatic steatosis has no correlation with liver-related or CV-related outcomes among diabetic patients after five years of follow-up.
      • Dunn M.A.
      • Behari J.
      • Rogal S.S.
      • et al.
      Hepatic steatosis in diabetic patients does not predict adverse liver-related or cardiovascular outcomes.
      • 3)
        Colorectal neoplasia
      Most of the data linking colorectal neoplasia and NAFLD has come out of Asian countries.
      • Lin X.F.
      • Shi K.Q.
      • You J.
      • et al.
      Increased risk of colorectal malignant neoplasm in patients with nonalcoholic fatty liver disease: a large study.
      • Lee T.
      • Yun K.E.
      • Chang Y.
      • et al.
      Risk of colorectal neoplasia according to fatty liver severity and presence of gall bladder polyps.
      • Ze E.Y.
      • Kim B.J.
      • Jun D.H.
      • Kim J.G.
      • Kang H.
      • Lee D.Y.
      The fatty liver index: a simple and accurate predictor of colorectal adenoma in an average-risk population.
      A recent study from the USA found a higher rate of polyp (43%) and adenoma (22%) detection (almost ∼twofold higher risk) in patients with NAFLD undergoing liver transplantation.
      • Bhatt B.D.
      • Lukose T.
      • Siegel A.B.
      • Brown Jr., R.S.
      • Verna E.C.
      Increased risk of colorectal polyps in patients with non-alcoholic fatty liver disease undergoing liver transplant evaluation.
      Similar reports have emerged from Europe as well.
      • Stadlmayr A.
      • Aigner E.
      • Steger B.
      • et al.
      Nonalcoholic fatty liver disease: an independent risk factor for colorectal neoplasia.
      Whether the increased risk of colorectal neoplasia is related to NAFLD or its association is related to diabetes is a matter of debate, and hopefully, future research in this area will answer these and other mechanistic questions.
      • Herrigel D.J.
      • Moss R.A.
      Diabetes mellitus as a novel risk factor for gastrointestinal malignancies.
      A recent meta-analysis of observational studies (involving asymptomatic individuals of predominantly Asian descent undergoing screening colonoscopy) suggested that NAFLD (detected by imaging or biopsy) is independently associated with a moderately increased prevalence and incidence of colorectal adenomas and cancer.
      • Mantovani A.
      • Dauriz M.
      • Byrne C.D.
      • et al.
      Association between nonalcoholic fatty liver disease and colorectal tumours in asymptomatic adults undergoing screening colonoscopy: a systematic review and meta-analysis.
      However, the observational design of these studies does not allow for inferring a causal relationship as the possibility of residual confounding by some unmeasured factors cannot be ruled out. More prospective studies, particularly in European and American individuals, and mechanistic studies are required to better understand the association between NAFLD and colonic carcinogenesis.
      • 4)
        Osteoporosis/osteopenia
      Although deterioration of bone homeostasis in patients with NAFLD is commonly observed, its etiology has not been fully elucidated yet. A recent study from the USA showed relationship between NAFLD with high alanine aminotransferase and lower BMD in the general US population.
      • Umehara T.
      Nonalcoholic fatty liver disease with elevated alanine aminotransferase levels is negatively associated with bone mineral density: cross-sectional study in U.S. adults.
      Chronic inflammation, vitamin D3, growth hormone, insulin-like growth factor 1, osteopontin, fetuin-A, irisin, osteocalcin, and osteoprotegerin from osteoblasts have been proposed as mediators of mutual interactions among the skeleton, fatty tissue, and liver leading to osteoporosis.
      • Filip R.
      • Radzki R.P.
      • Bienko M.
      Novel insights into the relationship between nonalcoholic fatty liver disease and osteoporosis.
      A study from Italy has shown independent associations between (a) low BMD and PNPLA3 CG + GG genotype; (b) low BMD and NASH; and (c) PNPLA3 CG + GG genotype and NASH, providing support for a causal relationship between NASH and low BMD.
      • Mosca A.
      • Fintini D.
      • Scorletti E.
      • et al.
      Relationship between non-alcoholic steatohepatitis, PNPLA3 I148M genotype and bone mineral density in adolescents.
      An earlier meta-analysis concluded that there is controversy regarding the effect of NAFLD on BMD. Further longitudinal studies that assess the effects of these two conditions are required to exclude the confounding effect of BMI on BMD. Although to date there are still many issues that have not been elucidated, growing evidence suggests that screening and surveillance for low bone mineral density in patients with NAFLD should be considered in future strategies and guidelines for NAFLD management.

      Economic Impact and Health-care Burden of NAFLD

      Estes et al. used the Markov model and METAVIR fibrosis stage of advanced liver disease to study the progression of liver disease in patients with NAFLD and NASH. According to this study, the total estimated cases of NAFLD is likely to increase from 83.1 million (2015) to 100.9 million by 2030 in the United States and NASH cases from 16.52 million (2015) to 27 million in 2030. A cross-sectional study using National Health and Nutrition Examination Survery data showed that among individuals with NAFLD, there was 23.8% prevalence of ≥F2 fibrosis and 2.3%–9.7% prevalence of ≥F3 fibrosis.
      • Wong R.J.
      • Liu B.
      • Bhuket T.
      Significant burden of nonalcoholic fatty liver disease with advanced fibrosis in the US: a cross-sectional analysis of 2011-2014 National Health and Nutrition Examination Survey.
      As the liver fibrosis cases increase, patients needing liver transplants are expected to increase as well. Lifetime costs of all patients with NASH in the US in 2017 were estimated to be $222.6 billion, and the cost of the advanced NASH population was estimated around $95.4 billion.
      • Younossi Z.M.
      • Tampi R.
      • Priyadarshini M.
      • Nader F.
      • Younossi I.M.
      • Racila A.
      Burden of illness and economic model for patients with non-alcoholic steatohepatitis (NASH) in the United States.
      Cirrhosis-related mortality secondary to NAFLD increased from 2007 to 2016 with an annual percentage change (APC) of 15.4%.
      • Kim D.
      • Li A.A.
      • Perumpail B.J.
      • et al.
      Changing trends in etiology- and ethnicity-based annual mortality rates of cirrhosis and hepatocellular carcinoma in the United States.
      The number of patients with NAFLD-related liver disease presenting to the emergency department has nearly doubled from 6% in 2005 to 11.9% in 2011.
      • Bush H.
      • Golabi P.
      • Otgonsuren M.
      • Rafiq N.
      • Venkatesan C.
      • Younossi Z.M.
      Nonalcoholic fatty liver is contributing to the increase in cases of liver disease in US emergency departments.
      A population-based cohort study in Olmsted County, Minnesota, including patients with NAFLD confirmed that survival in patients with NAFLD was lower than the expected survival for the general population. Higher mortality was associated with age (hazard ratio per decade 2.2), impaired glucose (hazard ratio of 2.6), and cirrhosis (hazard ratio of 3.1).
      • Adams L.A.
      • Lymp J.F.
      • St Sauver J.
      • et al.
      The natural history of nonalcoholic fatty liver disease: a population-based cohort study.
      Liver disease was the third leading cause of death in this patient population.
      • Adams L.A.
      • Lymp J.F.
      • St Sauver J.
      • et al.
      The natural history of nonalcoholic fatty liver disease: a population-based cohort study.
      As per US Census and National Center for Health Statistics mortality records, age-standardized mortality increased in patients with nonalcoholic liver disease from an APC of 6.1% in 2007–2013 to APC of 11.3% from 2013–2016.
      • Kim D.
      • Li A.A.
      • Gadiparthi C.
      • et al.
      Changing trends in etiology-based annual mortality from chronic liver disease, from 2007 through 2016.
      Usually, in patients with NAFLD, CVD represents the leading cause of death, followed by cancer-related and then liver-related mortality. Patients with NASH have higher risk of liver-related mortality than patients without NASH.
      • Stepanova M.
      • Rafiq N.
      • Makhlouf H.
      • et al.
      Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD).
      Patients with cryptogenic cirrhosis had more admission days in hospital for nonliver-related events like cardiovascular, cerebrovascular, and endocrine diseases compared to patients with noncryptogenic cirrhosis.
      • Mohammed O.K.
      • Mahadeva S.
      Clinical outcomes of cryptogenic compared with non-cryptogenic cirrhosis: a retrospective cohort study.
      A population-based cohort study conducted in Finland included 3 groups of patients with nonfatty liver disease, moderate fatty liver disease, and severe fatty liver disease, wherein patients with severe fatty liver disease had higher mortality and morbidity related to coronary artery disease independent of all traditional risk factors.
      • Pisto P.
      • Santaniemi M.
      • Bloigu R.
      • Ukkola O.
      • Kesaniemi Y.A.
      Fatty liver predicts the risk for cardiovascular events in middle-aged population: a population-based cohort study.
      The Framingham Risk Score accurately predicts coronary heart disease risk in patients with NAFLD and could help patients get an early intervention to reduce coronary events.
      • Treeprasertsuk S.
      • Leverage S.
      • Adams L.A.
      • Lindor K.D.
      • St Sauver J.
      • Angulo P.
      The Framingham risk score and heart disease in nonalcoholic fatty liver disease.

      Hepatocellular Carcinoma in Patients with NAFLD

      Hepatocellular carcinoma is the fourth deadliest cancer in the United States, and its annual incidence and death rate has been increasing by approximately 2.5% per year for the last two decades.
      • Tripathy S.R.
      • Mishra S.S.
      • Deo R.C.
      • Mohanta I.
      • Das D.
      • Satapathy M.C.
      Trochlear nerve neurofibroma in a clinically NF-1-Negative patient; a case report and review of literature.
       NAFLD/NASH is becoming a major cause of hepatocellular carcinoma in the United States and is associated with more advanced presentation and higher mortality.
      • Younossi Z.M.
      • Otgonsuren M.
      • Henry L.
      • et al.
      Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009.
      However, regrettably, patients with NASH-HCC are significantly less likely to receive Model for End-stage Liver Disease (MELD) exception points than patients with other etiologies of hepatocellular carcinoma.
      • Young K.
      • Aguilar M.
      • Gish R.
      • et al.
      Lower rates of receiving model for end-stage liver disease exception and longer time to transplant among nonalcoholic steatohepatitis hepatocellular carcinoma.
      Several factors play a role in carcinogenesis and progression of NASH to HCC.
      • Cholankeril G.
      • Patel R.
      • Khurana S.
      • Satapathy S.K.
      Hepatocellular carcinoma in non-alcoholic steatohepatitis: current knowledge and implications for management.
      Insulin resistance, damage of hepatocytes due to free fatty acids and adipokines, oxidative stress,
      • Yang S.
      • Zhu H.
      • Li Y.
      • et al.
      Mitochondrial adaptations to obesity-related oxidant stress.
      and inflammatory cytokines causing suppression of p53 tumor suppressor genes
      • Hu W.
      • Feng Z.
      • Eveleigh J.
      • et al.
      The major lipid peroxidation product, trans-4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in hepatocellular carcinoma.
      all cause progression of NAFLD to hepatocellular carcinoma. Interestingly, these pathophysiologic processes start at the stage of steatosis, and many Western studies have found hepatocellular carcinoma in early stages of steatosis even in noncirrhotic patients. A study conducted at the V.A. health system in Texas, United States, involving 1500 patients showed a strong association of NASH without cirrhosis with hepatocellular carcinoma.
      • Mittal S.
      • El-Serag H.B.
      • Sada Y.H.
      • et al.
      Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease.

      Liver Transplant in Patients with NAFLD

      Per a recent report, NASH has become the number one reason for liver transplantation in women and remains the second most common etiology in general for patients on liver transplant waitlist in the United States.
      • Wong R.J.
      • Aguilar M.
      • Cheung R.
      • et al.
      Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States.
      • Noureddin M.
      • Vipani A.
      • Bresee C.
      • et al.
      NASH leading cause of liver transplant in women: updated analysis of indications for liver transplant and ethnic and gender variances.
      The number of new waitlist registrants with NASH increased by 170% (804–2174) from 2004 to 2013. However, these patients have a lower 90-day survival and are less likely to receive a liver transplant.
      • Wong R.J.
      • Aguilar M.
      • Cheung R.
      • et al.
      Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States.
       Patients with NASH have significant diabetes, hypertension, and obesity and also seem to be older, which puts them at increased risk of mortality while waiting for a liver transplant.
      • Kemmer N.
      • Neff G.W.
      • Franco E.
      • et al.
      Nonalcoholic fatty liver disease epidemic and its implications for liver transplantation.
      The post-LT survival rate in NASH seems to be excellent with 88% survival at 1 year, 82% at 3 years, and 77% at 5 years, which is comparable to LT performed for other liver diseases.
      • Afzali A.
      • Berry K.
      • Ioannou G.N.
      Excellent posttransplant survival for patients with nonalcoholic steatohepatitis in the United States.
      Patients with normal renal function are at lower risk of mortality after liver transplant compared to patients with severe renal dysfunction in NASH group.
      • Molnar M.Z.
      • Joglekar K.
      • Jiang Y.
      • et al.
      Association of pre-transplant renal function with liver graft and patient survival after liver transplantation in patients with nonalcoholic steatohepatitis.
      On the other hand, a German group reported higher mortality, postoperative complications, and decreased graft survival in patients transplanted for NASH as they are associated with obesity and diabetes.
      • Heuer M.
      • Kaiser G.M.
      • Kahraman A.
      • et al.
      Liver transplantation in nonalcoholic steatohepatitis is associated with high mortality and post-transplant complications: a single-center experience.
      Despite this complex relation between metabolic risk factors and graft survival, it is very important to optimize risk factors as they play a significant role in post-LT cardiovascular events and development of recurrent NASH after liver transplant. Cardiovascular events, although common in the postoperative period in patients with NASH after liver transplant, do not seem to affect overall mortality.
      • Vanwagner L.B.
      • Bhave M.
      • Te H.S.
      • Feinglass J.
      • Alvarez L.
      • Rinella M.E.
      Patients transplanted for nonalcoholic steatohepatitis are at increased risk for postoperative cardiovascular events.
      • Satapathy S.K.
      • Jiang Y.
      • Eason J.D.
      • et al.
      Cardiovascular mortality among liver transplant recipients with nonalcoholic steatohepatitis in the United States-a retrospective study.
      NAFLD recurrence after liver transplantation is a vexing problem, and its incidence has been reported to be anywhere between 15 and 100%.
      • Andrade A.
      • Cotrim H.P.
      • Bittencourt P.L.
      • Almeida C.G.
      • Sorte N.
      Nonalcoholic steatohepatitis in posttransplantation liver: review article.
      Post-transplant metabolic syndrome has multifactorial etiologies, although adverse effect profile of immunosuppressive agents (steroids, calcineurin inhibitors, mTOR inhibitors, and so on) and lack of adherence to lifestyle modifications are its major contributors. Physicians ought to educate their patients on the pivotal role of diet and exercise after liver transplantation and attempt risk factor modification (e.g., control of high blood pressure, diabetes, dyslipidemia, obesity, CKD) with appropriate counseling and pharmacotherapy.

      Burning Issues in NAFLD Care

      With a lack of widespread awareness among primary care physicians of its existence, associated complications and impact on health care and absence of screening guidelines from major medical societies such as American Association for the Study of Liver Diseases and European Association for the Study of the Liver, hitherto, which recognized incidence of NAFLD are likely the tip of the proverbial ‘iceberg’. The problem gets compounded by the lack of Food and Drug Administration–approved treatment for this condition and our sole reliance on human/patient behavior to practice lifestyle modifications which require lifelong dietary self-control and unremitting self-discipline to participate in regular physical activity, which fails too often to be relied upon as the principal treatment option for this entity. Lastly, given rising rates of NAFLD in general Western population, there is growing concern that we will soon run out of ‘suitable donors’ for deceased or living donor liver transplantation for NAFLD as hepatic steatosis is associated with risk of primary nonfunction/early allograft dysfunction. A summary of the magnitude of NAFLD is presented in Table 1.
      Table 1Magnitude of NAFLD—Summary of Western Perspective.
      Magnitude of NAFLDFrequencies
      Frequencies reported unless stated otherwise.
      Reference
      Prevalence of NAFLD in the USA24%2, 6
      Prevalence of NAFLD in South America31%2, 6
      Prevalence of NAFLD in Europe23.71%2, 6
      NAFLD prevalence in Hispanic-Americans24.1%2, 6
      NALFD prevalence in African Americans13.5%2, 6
      Lifetime cost of patients with NASH (in 2017 US$)222.63
      Prevalence of NAFLD risk factors
       Obesity39.8%21
       Diabetes9.8%23
       Chronic kidney disease6.9%70
       Obstructive sleep apnea6.5%41, 42
      Leading indication for liver transplantation in women in the USANAFLD112
      Second leading cause of liver transplantation in the USANAFLD111
      Post-LT survival for NASH at 1 year88%114
      Post-LT survival for NASH at 3 years82%114
      Post-LT survival for NASH at 5 years77%114
      NAFLD recurrence after LT15–100%119
      NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.
      a Frequencies reported unless stated otherwise.
      In summary, NAFLD represents a spectrum of diseases varying from hepatic steatosis to cirrhosis and hepatocellular carcinoma which is taking the shape of a rapidly rising epidemic, which will substantially encumber the health-care system in the United States and all over the world. Rising trends of metabolic risk factors will further worsen the magnitude of NAFLD, leading to further complications and increasing economic burden. Public health efforts should be aimed at forming policies and guidelines to control and prepare for the imminent onslaught of this pervasive noncommunicable disease.

      Author contributions

      Sanjaya K. Satapathy conceptualized the manuscript, and along with Naga Swetha Samji, and Rajanshu Verma drafted the manuscript. All other authors participated in the critical revision of the manuscript for important intellectual content.

      Conflicts of interest

      The authors have none to declare.

      References

        • Hales C.M.
        • Carroll M.D.
        • Fryar C.D.
        • Ogden C.L.
        Prevalence of obesity among adults and youth: United States, 2015-2016.
        NCHS data brief. 2017; : 1-8
        • Younossi Z.M.
        • Koenig A.B.
        • Abdelatif D.
        • Fazel Y.
        • Henry L.
        • Wymer M.
        Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.
        Hepatology. 2016; 64: 73-84
        • Younossi Z.M.
        • Tampi R.
        • Priyadarshini M.
        • Nader F.
        • Younossi I.M.
        • Racila A.
        Burden of illness and economic model for patients with non-alcoholic steatohepatitis (NASH) in the United States.
        Hepatology. 2018; 69
        • Uhanova J.
        • Minuk G.
        • Lopez Ficher F.
        • Chandok N.
        Nonalcoholic fatty liver disease in Canadian first nations and non-first nations patients.
        Chin J Gastroenterol Hepatol. 2016; 2016: 6420408
        • Andrade G.C.
        • Fujise L.H.
        • Santana J.E.F.
        • Oliveira F.
        • Silva Rde C.
        Non-alcoholic fatty liver disease (NAFLD) in different populations: a clinical and epidemiological study - sample of Sao Jose do Rio Preto.
        Rev Assoc Med Bras. 2016; 62: 218-226
        • Younossi Z.
        • Anstee Q.M.
        • Marietti M.
        • et al.
        Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.
        Nat Rev Gastroenterol Hepatol. 2018; 15: 11-20
        • Tomic D.
        • Kemp W.W.
        • Roberts S.K.
        Nonalcoholic fatty liver disease: current concepts, epidemiology and management strategies.
        Eur J Gastroenterol Hepatol. 2018; 30: 1103-1115
        • Andronescu C.I.
        • Purcarea M.R.
        • Babes P.A.
        Nonalcoholic fatty liver disease: epidemiology, pathogenesis and therapeutic implications.
        J Med Life. 2018; 11: 20-23
        • Lazo M.
        • Hernaez R.
        • Eberhardt M.S.
        • et al.
        Prevalence of nonalcoholic fatty liver disease in the United States: the third national health and nutrition examination survey, 1988-1994.
        Am J Epidemiol. 2013; 178: 38-45
        • Bambha K.
        • Belt P.
        • Abraham M.
        • et al.
        Ethnicity and nonalcoholic fatty liver disease.
        Hepatology. 2012; 55: 769-780
        • Vilar L.
        • Oliveira C.P.
        • Faintuch J.
        • et al.
        High-fat diet: a trigger of non-alcoholic steatohepatitis? Preliminary findings in obese subjects.
        Nutrition. 2008; 24: 1097-1102
        • Assy N.
        • Nassar F.
        • Nasser G.
        • Grosovski M.
        Olive oil consumption and non-alcoholic fatty liver disease.
        World J Gastroenterol : WJG. 2009; 15: 1809-1815
        • Capanni M.
        • Calella F.
        • Biagini M.R.
        • et al.
        Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study.
        Aliment Pharmacol Ther. 2006; 23: 1143-1151
        • Andersen C.J.
        • Fernandez M.L.
        Dietary strategies to reduce metabolic syndrome.
        Rev Endocr Metab Disord. 2013; 14: 241-254
        • Martinez-Gonzalez M.A.
        • Martin-Calvo N.
        The major European dietary patterns and metabolic syndrome.
        Rev Endocr Metab Disord. 2013; 14: 265-271
        • Esposito K.
        • Kastorini C.M.
        • Panagiotakos D.B.
        • Giugliano D.
        Mediterranean diet and metabolic syndrome: an updated systematic review.
        Rev Endocr Metab Disord. 2013; 14: 255-263
        • Gelli C.
        • Tarocchi M.
        • Abenavoli L.
        • Di Renzo L.
        • Galli A.
        • De Lorenzo A.
        Effect of a counseling-supported treatment with the Mediterranean diet and physical activity on the severity of the non-alcoholic fatty liver disease.
        World J Gastroenterol. 2017; 23: 3150-3162
        • Kubik J.F.
        • Gill R.S.
        • Laffin M.
        • Karmali S.
        The impact of bariatric surgery on psychological health.
        J obes. 2013; 2013: 837989
      1. Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organization technical report series 2000, 894. 2000: 1-253
        • Finucane M.M.
        • Stevens G.A.
        • Cowan M.J.
        • et al.
        National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants.
        Lancet. 2011; 377: 557-567
      2. Prevalence of obesity among adults and youth: United States, 2015–2016. 2017
        • Block J.P.
        • Subramanian S.V.
        • Christakis N.A.
        • O'Malley A.J.
        Population trends and variation in body mass index from 1971 to 2008 in the Framingham heart study offspring cohort.
        PLoS One. 2013; 8e63217
      3. National diabetes Statistics report 2017: estimates of diabetes and its burden in the United States. 2017
        • Williams C.D.
        • Stengel J.
        • Asike M.I.
        • et al.
        Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study.
        Gastroenterology. 2011; 140: 124-131
        • Bellentani S.
        • Saccoccio G.
        • Masutti F.
        • et al.
        Prevalence of and risk factors for hepatic steatosis in Northern Italy.
        Ann Intern Med. 2000; 132: 112-117
        • Chalasani N.
        • Younossi Z.
        • Lavine J.E.
        • et al.
        The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
        Hepatology. 2018; 67: 328-357
        • Wang A.Y.
        • Dhaliwal J.
        • Mouzaki M.
        Lean non-alcoholic fatty liver disease.
        Clin Nutr. 2018; 38
        • Younossi Z.M.
        • Stepanova M.
        • Negro F.
        • et al.
        Nonalcoholic fatty liver disease in lean individuals in the United States.
        Medicine (Baltim). 2012; 91: 319-327
        • Ha Y.
        • Seo N.
        • Shim J.H.
        • et al.
        Intimate association of visceral obesity with non-alcoholic fatty liver disease in healthy asians: a case-control study.
        J Gastroenterol Hepatol. 2015; 30
        • Lassailly G.
        • Caiazzo R.
        • Buob D.
        • et al.
        Bariatric surgery reduces features of non-alcoholic steatohepatitis in morbidly obese patients.
        Gastroenterology. 2015; 149
        • Lee Y.
        • Doumouras A.G.
        • Yu J.
        • et al.
        Complete resolution of nonalcoholic fatty liver disease after bariatric surgery: a systematic review and meta-analysis.
        Clin Gastroenterol Hepatol. 2018; 17
        • Tilg H.
        • Moschen A.R.
        • Roden M.
        NAFLD and diabetes mellitus.
        Nat Rev Gastroenterol Hepatol. 2017; 14: 32-42
        • Loomba R.
        • Abraham M.
        • Unalp A.
        • et al.
        Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis.
        Hepatology. 2012; 56: 943-951
        • Angulo P.
        • Hui J.M.
        • Marchesini G.
        • et al.
        The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD.
        Hepatology. 2007; 45: 846-854
        • Neuschwander-Tetri B.A.
        • Clark J.M.
        • Bass N.M.
        • et al.
        Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease.
        Hepatology. 2010; 52: 913-924
        • Angulo P.
        • Keach J.C.
        • Batts K.P.
        • Lindor K.D.
        Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis.
        Hepatology. 1999; 30: 1356-1362
        • Marchesini G.
        • Brizi M.
        • Morselli-Labate A.M.
        • et al.
        Association of nonalcoholic fatty liver disease with insulin resistance.
        Am J Med. 1999; 107: 450-455
        • Powell E.E.
        • Cooksley W.G.
        • Hanson R.
        • Searle J.
        • Halliday J.W.
        • Powell L.W.
        The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years.
        Hepatology. 1990; 11: 74-80
        • El-Serag H.B.
        • Tran T.
        • Everhart J.E.
        Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.
        Gastroenterology. 2004; 126: 460-468
        • Bugianesi E.
        • Leone N.
        • Vanni E.
        • et al.
        Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.
        Gastroenterology. 2002; 123: 134-140
        • Young T.
        • Palta M.
        • Dempsey J.
        • Skatrud J.
        • Weber S.
        • Badr S.
        The occurrence of sleep-disordered breathing among middle-aged adults.
        N Engl J Med. 1993; 328: 1230-1235
        • Vgontzas A.N.
        • Tan T.L.
        • Bixler E.O.
        • Martin L.F.
        • Shubert D.
        • Kales A.
        Sleep apnea and sleep disruption in obese patients.
        Arch Intern Med. 1994; 154: 1705-1711
        • Tanne F.
        • Gagnadoux F.
        • Chazouilleres O.
        • et al.
        Chronic liver injury during obstructive sleep apnea.
        Hepatology. 2005; 41: 1290-1296
        • Musso G.
        • Cassader M.
        • Olivetti C.
        • Rosina F.
        • Carbone G.
        • Gambino R.
        Association of obstructive sleep apnoea with the presence and severity of non-alcoholic fatty liver disease. A systematic review and meta-analysis.
        Obes Rev. 2013; 14: 417-431
        • Newton J.L.
        • Jones D.E.
        • Henderson E.
        • et al.
        Fatigue in non-alcoholic fatty liver disease (NAFLD) is significant and associates with inactivity and excessive daytime sleepiness but not with liver disease severity or insulin resistance.
        Gut. 2008; 57: 807-813
        • Singh H.
        • Pollock R.
        • Uhanova J.
        • Kryger M.
        • Hawkins K.
        • Minuk G.Y.
        Symptoms of obstructive sleep apnea in patients with nonalcoholic fatty liver disease.
        Dig Dis Sci. 2005; 50: 2338-2343
        • Paschetta E.
        • Belci P.
        • Alisi A.
        • Liccardo D.
        • Cutrera R.
        • Musso G.
        OSAS-related Inflammatory Mechanisms of Liver Injury in Nonalcoholic Fatty Liver Disease. 2015.
        2015: 815721
        • Ciftci T.U.
        • Kokturk O.
        • Bukan N.
        • Bilgihan A.
        The relationship between serum cytokine levels with obesity and obstructive sleep apnea syndrome.
        Cytokine. 2004; 28: 87-91
        • Ryan S.
        • Taylor C.T.
        • McNicholas W.T.
        Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome.
        Circulation. 2005; 112: 2660-2667
        • Christou K.
        • Markoulis N.
        • Moulas A.N.
        • Pastaka C.
        • Gourgoulianis K.I.
        Reactive oxygen metabolites (ROMs) as an index of oxidative stress in obstructive sleep apnea patients.
        Sleep breathing = Schlaf & Atmung. 2003; 7: 105-110
        • Musso G.
        • Olivetti C.
        • Cassader M.
        • Gambino R.
        Obstructive sleep apnea-hypopnea syndrome and nonalcoholic fatty liver disease: emerging evidence and mechanisms.
        Semin Liver Dis. 2012; 32: 49-64
        • Piguet A.C.
        • Stroka D.
        • Zimmermann A.
        • Dufour J.F.
        Hypoxia aggravates non-alcoholic steatohepatitis in mice lacking hepatocellular PTEN.
        Clin Sci (Lond). 2010; 118: 401-410
        • Aron-Wisnewsky J.
        • Minville C.
        • Tordjman J.
        • et al.
        Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese.
        J Hepatol. 2012; 56: 225-233
        • Mishra P.
        • Nugent C.
        • Afendy A.
        • et al.
        Apnoeic-hypopnoeic episodes during obstructive sleep apnoea are associated with histological nonalcoholic steatohepatitis.
        Liver Int. 2008; 28: 1080-1086
        • Daltro C.
        • Cotrim H.P.
        • Alves E.
        • et al.
        Nonalcoholic fatty liver disease associated with obstructive sleep apnea: just a coincidence?.
        Obes Surg. 2010; 20: 1536-1543
        • Kallwitz E.R.
        • Herdegen J.
        • Madura J.
        • Jakate S.
        • Cotler S.J.
        Liver enzymes and histology in obese patients with obstructive sleep apnea.
        J Clin Gastroenterol. 2007; 41: 918-921
        • Polotsky V.Y.
        • Patil S.P.
        • Savransky V.
        • et al.
        Obstructive sleep apnea, insulin resistance, and steatohepatitis in severe obesity.
        Am J Respir Crit Care Med. 2009; 179: 228-234
        • Campos G.M.
        • Bambha K.
        • Vittinghoff E.
        • et al.
        A clinical scoring system for predicting nonalcoholic steatohepatitis in morbidly obese patients.
        Hepatology. 2008; 47: 1916-1923
        • Corey K.E.
        • Misdraji J.
        • Gelrud L.
        • et al.
        Obstructive Sleep Apnea Is Associated with Nonalcoholic Steatohepatitis and Advanced Liver Histology.
        Digestive diseases and sciences, 2015
        • Danford C.J.
        • Yao Z.M.
        • Jiang Z.G.
        Non-alcoholic fatty liver disease: a narrative review of genetics.
        J Biomed Res. 2018; 32: 389-400
        • Romeo S.
        • Kozlitina J.
        • Xing C.
        • et al.
        Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.
        Nat Genet. 2008; 40: 1461-1465
        • Sookoian S.
        • Pirola C.J.
        Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease.
        Hepatology. 2011; 53: 1883-1894
        • Kovalic A.J.
        • Banerjee P.
        • Tran Q.T.
        • Singal A.K.
        • Satapathy S.K.
        Genetic and epigenetic culprits in the pathogenesis of nonalcoholic fatty liver disease.
        J. Clin exp hepatol. 2018; 8: 390-402
        • Xu R.
        • Tao A.
        • Zhang S.
        • Deng Y.
        • Chen G.
        Association between patatin-like phospholipase domain containing 3 gene (PNPLA3) polymorphisms and nonalcoholic fatty liver disease: a HuGE review and meta-analysis.
        Sci Rep. 2015; 5: 9284
        • Verrijken A.
        • Beckers S.
        • Francque S.
        • et al.
        A gene variant of PNPLA3, but not of APOC3, is associated with histological parameters of NAFLD in an obese population.
        Obesity. 2013; 21: 2138-2145
        • Singal A.G.
        • Manjunath H.
        • Yopp A.C.
        • et al.
        The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis.
        Am J Gastroenterol. 2014; 109: 325-334
        • Chamoun Z.
        • Vacca F.
        • Parton R.G.
        • Gruenberg J.
        PNPLA3/adiponutrin functions in lipid droplet formation.
        Biol Cell. 2013; 105: 219-233
        • He S.
        • McPhaul C.
        • Li J.Z.
        • et al.
        A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis.
        J Biol Chem. 2010; 285: 6706-6715
        • Huang Y.
        • Cohen J.C.
        • Hobbs H.H.
        Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease.
        J Biol Chem. 2011; 286: 37085-37093
        • Murphy D.
        • McCulloch C.E.
        • Lin F.
        • et al.
        Trends in prevalence of chronic kidney disease in the United States.
        Ann Intern Med. 2016; 165: 473-481
        • Musso G.
        • Gambino R.
        • Tabibian J.H.
        • et al.
        Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis.
        PLoS Med. 2014; 11e1001680
        • Mantovani A.
        • Zaza G.
        • Byrne C.D.
        • et al.
        Nonalcoholic fatty liver disease increases risk of incident chronic kidney disease: a systematic review and meta-analysis.
        Metabolism. 2018; 79: 64-76
        • Paik J.
        • Golabi P.
        • Younoszai Z.
        • Mishra A.
        • Trimble G.
        • Younossi Z.M.
        Chronic kidney disease is independently associated with increased mortality in patients with non-alcoholic fatty liver disease.
        Liver Int. 2018; 39
        • Chinnadurai R.
        • Ritchie J.
        • Green D.
        • Kalra P.A.
        Non-alcoholic fatty liver disease and clinical outcomes in chronic kidney disease.
        Nephrol Dial Transpl. 2018; 34
        • Molnar M.Z.
        • Joglekar K.
        • Jiang Y.
        • et al.
        Association of pre-transplant renal function with liver graft and patient survival after liver transplantation in patients with nonalcoholic steatohepatitis.
        Liver Transpl. 2018; 25
        • Luo J.
        • Xu L.
        • Li J.
        • Zhao S.
        Nonalcoholic fatty liver disease as a potential risk factor of cardiovascular disease.
        Eur J Gastroenterol Hepatol. 2015; 27: 193-199
        • Fracanzani A.L.
        • Tiraboschi S.
        • Pisano G.
        • et al.
        Progression of carotid vascular damage and cardiovascular events in non-alcoholic fatty liver disease patients compared to the general population during 10 years of follow-up.
        Atherosclerosis. 2016; 246: 208-213
        • Zeb I.
        • Li D.
        • Budoff M.J.
        • et al.
        Nonalcoholic fatty liver disease and incident cardiac events: the multi-ethnic study of Atherosclerosis.
        J Am Coll Cardiol. 2016; 67: 1965-1966
        • Pisto P.
        • Santaniemi M.
        • Bloigu R.
        • Ukkola O.
        • Kesaniemi Y.A.
        Fatty liver predicts the risk for cardiovascular events in middle-aged population: a population-based cohort study.
        BMJ open. 2014; 4e004973
        • Pickhardt P.J.
        • Hahn L.
        • Munoz del Rio A.
        • Park S.H.
        • Reeder S.B.
        • Said A.
        Natural history of hepatic steatosis: observed outcomes for subsequent liver and cardiovascular complications.
        AJR American journal of roentgenology. 2014; 202: 752-758
        • Mellinger J.L.
        • Pencina K.M.
        • Massaro J.M.
        • et al.
        Hepatic steatosis and cardiovascular disease outcomes: an analysis of the Framingham Heart Study.
        J Hepatol. 2015; 63: 470-476
        • Matteoni C.A.
        • Younossi Z.M.
        • Gramlich T.
        • Boparai N.
        • Liu Y.C.
        • McCullough A.J.
        Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.
        Gastroenterology. 1999; 116: 1413-1419
        • Ekstedt M.
        • Franzen L.E.
        • Mathiesen U.L.
        • et al.
        Long-term follow-up of patients with NAFLD and elevated liver enzymes.
        Hepatology. 2006; 44: 865-873
        • Rafiq N.
        • Bai C.
        • Fang Y.
        • et al.
        Long-term follow-up of patients with nonalcoholic fatty liver.
        Clin Gastroenterol Hepatol. 2009; 7: 234-238
        • Dunn M.A.
        • Behari J.
        • Rogal S.S.
        • et al.
        Hepatic steatosis in diabetic patients does not predict adverse liver-related or cardiovascular outcomes.
        Liver Int. 2013; 33: 1575-1582
        • Lin X.F.
        • Shi K.Q.
        • You J.
        • et al.
        Increased risk of colorectal malignant neoplasm in patients with nonalcoholic fatty liver disease: a large study.
        Mol Biol Rep. 2014; 41: 2989-2997
        • Lee T.
        • Yun K.E.
        • Chang Y.
        • et al.
        Risk of colorectal neoplasia according to fatty liver severity and presence of gall bladder polyps.
        Dig Dis Sci. 2016; 61: 317-324
        • Ze E.Y.
        • Kim B.J.
        • Jun D.H.
        • Kim J.G.
        • Kang H.
        • Lee D.Y.
        The fatty liver index: a simple and accurate predictor of colorectal adenoma in an average-risk population.
        Dis Colon Rectum. 2018; 61: 36-42
        • Bhatt B.D.
        • Lukose T.
        • Siegel A.B.
        • Brown Jr., R.S.
        • Verna E.C.
        Increased risk of colorectal polyps in patients with non-alcoholic fatty liver disease undergoing liver transplant evaluation.
        J Gastrointest Oncol. 2015; 6: 459-468
        • Stadlmayr A.
        • Aigner E.
        • Steger B.
        • et al.
        Nonalcoholic fatty liver disease: an independent risk factor for colorectal neoplasia.
        J Intern Med. 2011; 270: 41-49
        • Herrigel D.J.
        • Moss R.A.
        Diabetes mellitus as a novel risk factor for gastrointestinal malignancies.
        PGM (Postgrad Med). 2014; 126: 106-118
        • Mantovani A.
        • Dauriz M.
        • Byrne C.D.
        • et al.
        Association between nonalcoholic fatty liver disease and colorectal tumours in asymptomatic adults undergoing screening colonoscopy: a systematic review and meta-analysis.
        Metab Clin Exp. 2018; 87: 1-12
        • Umehara T.
        Nonalcoholic fatty liver disease with elevated alanine aminotransferase levels is negatively associated with bone mineral density: cross-sectional study in U.S. adults.
        PLoS One. 2018; 13e0197900
        • Filip R.
        • Radzki R.P.
        • Bienko M.
        Novel insights into the relationship between nonalcoholic fatty liver disease and osteoporosis.
        Clin Interv Aging. 2018; 13: 1879-1891
        • Mosca A.
        • Fintini D.
        • Scorletti E.
        • et al.
        Relationship between non-alcoholic steatohepatitis, PNPLA3 I148M genotype and bone mineral density in adolescents.
        Liver Int. 2018; 38: 2301-2308
        • Wong R.J.
        • Liu B.
        • Bhuket T.
        Significant burden of nonalcoholic fatty liver disease with advanced fibrosis in the US: a cross-sectional analysis of 2011-2014 National Health and Nutrition Examination Survey.
        Aliment Pharmacol Ther. 2017; 46: 974-980
        • Kim D.
        • Li A.A.
        • Perumpail B.J.
        • et al.
        Changing trends in etiology- and ethnicity-based annual mortality rates of cirrhosis and hepatocellular carcinoma in the United States.
        Hepatology. 2018; 69
        • Bush H.
        • Golabi P.
        • Otgonsuren M.
        • Rafiq N.
        • Venkatesan C.
        • Younossi Z.M.
        Nonalcoholic fatty liver is contributing to the increase in cases of liver disease in US emergency departments.
        J Clin Gastroenterol. 2018; 53
        • Adams L.A.
        • Lymp J.F.
        • St Sauver J.
        • et al.
        The natural history of nonalcoholic fatty liver disease: a population-based cohort study.
        Gastroenterology. 2005; 129: 113-121
        • Kim D.
        • Li A.A.
        • Gadiparthi C.
        • et al.
        Changing trends in etiology-based annual mortality from chronic liver disease, from 2007 through 2016.
        Gastroenterology. 2018; 155: 1154-1163
        • Stepanova M.
        • Rafiq N.
        • Makhlouf H.
        • et al.
        Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD).
        Dig Dis Sci. 2013; 58: 3017-3023
        • Mohammed O.K.
        • Mahadeva S.
        Clinical outcomes of cryptogenic compared with non-cryptogenic cirrhosis: a retrospective cohort study.
        J Gastroenterol Hepatol. 2015; 30: 1423-1428
        • Treeprasertsuk S.
        • Leverage S.
        • Adams L.A.
        • Lindor K.D.
        • St Sauver J.
        • Angulo P.
        The Framingham risk score and heart disease in nonalcoholic fatty liver disease.
        Liver Int. 2012; 32: 945-950
        • Tripathy S.R.
        • Mishra S.S.
        • Deo R.C.
        • Mohanta I.
        • Das D.
        • Satapathy M.C.
        Trochlear nerve neurofibroma in a clinically NF-1-Negative patient; a case report and review of literature.
        World Neurosurg. 2016; 89 (732 e713-738)
        • Younossi Z.M.
        • Otgonsuren M.
        • Henry L.
        • et al.
        Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009.
        Hepatology. 2015; 62: 1723-1730
        • Young K.
        • Aguilar M.
        • Gish R.
        • et al.
        Lower rates of receiving model for end-stage liver disease exception and longer time to transplant among nonalcoholic steatohepatitis hepatocellular carcinoma.
        Liver Transpl. 2016; 22: 1356-1366
        • Cholankeril G.
        • Patel R.
        • Khurana S.
        • Satapathy S.K.
        Hepatocellular carcinoma in non-alcoholic steatohepatitis: current knowledge and implications for management.
        World J Hepatol. 2017; 9: 533-543
        • Yang S.
        • Zhu H.
        • Li Y.
        • et al.
        Mitochondrial adaptations to obesity-related oxidant stress.
        Arch Biochem Biophys. 2000; 378: 259-268
        • Hu W.
        • Feng Z.
        • Eveleigh J.
        • et al.
        The major lipid peroxidation product, trans-4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in hepatocellular carcinoma.
        Carcinogenesis. 2002; 23: 1781-1789
        • Mittal S.
        • El-Serag H.B.
        • Sada Y.H.
        • et al.
        Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease.
        Clin Gastroenterol Hepatol. 2016; 14: 124-131 e121
        • Wong R.J.
        • Aguilar M.
        • Cheung R.
        • et al.
        Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States.
        Gastroenterology. 2015; 148: 547-555
        • Noureddin M.
        • Vipani A.
        • Bresee C.
        • et al.
        NASH leading cause of liver transplant in women: updated analysis of indications for liver transplant and ethnic and gender variances.
        Am J Gastroenterol. 2018; 113: 1649-1659
        • Kemmer N.
        • Neff G.W.
        • Franco E.
        • et al.
        Nonalcoholic fatty liver disease epidemic and its implications for liver transplantation.
        Transplantation. 2013; 96: 860-862
        • Afzali A.
        • Berry K.
        • Ioannou G.N.
        Excellent posttransplant survival for patients with nonalcoholic steatohepatitis in the United States.
        Liver Transplant. 2012; 18: 29-37
        • Molnar M.Z.
        • Joglekar K.
        • Jiang Y.
        • et al.
        Association of pre-transplant renal function with liver graft and patient survival after liver transplantation in patients with nonalcoholic steatohepatitis.
        Liver Transplant. 2018; 25
        • Heuer M.
        • Kaiser G.M.
        • Kahraman A.
        • et al.
        Liver transplantation in nonalcoholic steatohepatitis is associated with high mortality and post-transplant complications: a single-center experience.
        Digestion. 2012; 86: 107-113
        • Vanwagner L.B.
        • Bhave M.
        • Te H.S.
        • Feinglass J.
        • Alvarez L.
        • Rinella M.E.
        Patients transplanted for nonalcoholic steatohepatitis are at increased risk for postoperative cardiovascular events.
        Hepatology. 2012; 56: 1741-1750
        • Satapathy S.K.
        • Jiang Y.
        • Eason J.D.
        • et al.
        Cardiovascular mortality among liver transplant recipients with nonalcoholic steatohepatitis in the United States-a retrospective study.
        Transpl Int. 2017; 30: 1051-1060
        • Andrade A.
        • Cotrim H.P.
        • Bittencourt P.L.
        • Almeida C.G.
        • Sorte N.
        Nonalcoholic steatohepatitis in posttransplantation liver: review article.
        Revista da Associacao Medica Brasileira (1992). 2018; 64: 187-194